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Biomedical subjects

R A Brown

Publications and source records attributed to R A Brown.

At least 73 records · Page 4Linked to original sources
PubMed2000

Innovations in allogeneic stem-cell transplantation.

Allogeneic bone marrow transplantation (BMT) is associated with prolonged periods of neutropenia and thrombocytopenia, which can lead to severe infections and bleeding complications. Transplantation-related side effects might be ameliorated by use of cytokine-mobilized peripheral blood progenitor cells (PBPC) Instead of bone marrow. We have studied PBPC mobilization and transplantation in more than 150 patients with high-risk hematologic malignancies. Normal donors can be sufficiently mobilized with granulocyte colony-stimulating factor (G-CSF), with 91% of G-CSF-stimulated normal donors producing more than 2 x 10(6) CD34+ cells/kg by a single apheresis. The combination of G-CSF plus granulocyte-macrophage colony-stimulating factor (GM-CSF) was more effective than mobilization with G-CSF alone. A clear relationship was seen between numbers of resting CD34+ cells premobilization and numbers of PBPC collected by apheresis, indicating that resting CD34+ cells might be used to predict mobilization results and identify donors who could benefit from more effective mobilization regimens. Transplantation of G-CSF-mobilized PBPC was associated with a more rapid engraftment than that observed for BMT. While engraftment was safe and acute graft-versus-host disease (aGvHD) rates were not increased over BMT, chronic GvHD rates were higher after PBPC transplantation. An additional PBPC infusion on day +3 resulted in a further shortening of neutropenia and thrombocytopenia. Incorporation of these innovative approaches with "minimal" conditioning regimens has resulted in near-complete elimination of fever, neutropenia, thrombocytopenia, and the need for antibiotics and RBC and platelet transfusions after allogeneic transplantation.

Animals↗
PubMed2000

Diminished cardiac contractile response to tetrahydropapaveroline in hypertension: role of beta-adrenoceptors and intracellular Ca(2+).

Tetrahydropapaveroline (THP), a condensation product of ethanol-derived acetaldehyde, potentiates cardiac function through a beta-adrenergic mechanism. It is well established that beta-adrenergic activity is markedly depressed in hypertension. However, little is known about the myocardial action of THP in hypertension. In this study, the effect of THP was examined using left ventricular papillary muscles and ventricular myocytes from 10-week-old normotensive (WKY) and spontaneously hypertensive (SHR) rats. The mechanical parameters evaluated include: peak tension developed (PTD), peak twitch amplitude (PTA), time-to-PTD/PTA (TPT/TPS), time-to-90% relaxation/relengthening (RT(90)/TR(90)), and the maximal velocities of contraction/shortening and relaxation/relengthening (+/-VT/+/-dL/dt). Intracellular Ca(2+) transients were measured as fura-2 fluorescence intensity changes (delta FFI). THP (0.01-100 microM) produced a concentration-dependent increase in myocardial contraction on muscles and myocytes from both groups of animals. However, preparations from the SHR group were generally less responsive to THP than their normotensive counterparts. The increase in contractility by THP was associated with increases in delta FFI and +/-VT, and shortening of TPT/TPS and RT(90)/TR(90). The role of beta-adrenoceptor(s) in the mechanism of action of THP was explored using specific beta-receptor subtype antagonists CGP 207.12A (beta(1)) and ICI 118,551 (beta(2)). In preparations from both WKY and SHR hearts, the THP-induced increase in cardiac contractility was either attenuated or blocked by CGP 207. 12A and ICI 118,551. These results indicate that THP exhibits a positive action on myocardial contraction that is mediated, in part, through both beta(1) and beta(2) adrenergic receptors. This cardiac inotropic response, however, is markedly diminished in hypertension, which is due possibly to alterations in beta-adrenergic signal transduction.

Adrenergic beta-Antagonists↗
PubMed2000

Determinants of attrition from cessation treatment in smokers with a history of major depressive disorder.

Attrition from smoking cessation treatment by individuals with a history of major depression was investigated. An investigation of preinclusion attrition examined differences between eligible smokers who did (n = 258) and did not (n = 100) attend an initial assessment session. Postinclusion attrition was investigated by comparing early dropouts (n = 33), late dropouts (n = 27), and treatment completers (n = 117). Those who failed to attend the assessment session were more likely to be female, to smoke cigarettes with higher nicotine content, and to have a history of psychotropic medication use. Early-treatment dropouts reported a higher smoking rate than late-treatment dropouts and endorsed more symptoms of depression than late dropouts and treatment completers. Results are compared with previous investigations of smoking cessation attrition, and implications for treatment and attrition prevention are discussed.

Adult↗
PubMed2000

A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma.

This randomized, controlled study compared the ability to mobilize and collect an optimal target yield of 5 x 10(6) CD34+ cells/kg using stem cell factor (SCF; 20 microg/kg/day) plus filgrastim (G-CSF; 10 microg/kg/day) vs filgrastim alone (10 microg/kg/day) in 102 patients diagnosed with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD), who were prospectively defined as being heavily pretreated. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield was reached, or until a maximum of five leukaphereses had been performed. Compared with the filgrastim-alone group (n = 54), the SCF plus filgrastim group (n = 48) showed an increase in the proportion of patients reaching the target yield within five leukaphereses (44% vs 17%, P = 0.002); reduction in the number of leukaphereses required to reach the target yield (P = 0.003); reduction in the proportion of patients failing to reach a minimum yield of 1 x 10(6) CD34+ cells/kg to proceed to transplant (16% vs 26%, P = NS); increase in the median yield of CD34+ cells per leukapheresis (0.73 x 10(6)/kg vs 0.48 x 10(6)/kg, P = 0.04); and an increase in the median total CD34+ cells collected within five leukaphereses (3.6 x 10(6)/kg vs 2.4 x 10(6)/kg, P = 0.05). All patients receiving SCF were premedicated (antihistamines and albuterol), and treatment was generally well tolerated. Five patients experienced severe mast cell-mediated reactions, none of which were life-threatening. In this study of heavily pretreated lymphoma patients, SCF plus filgrastim was more effective than filgrastim alone for mobilizing PBPC for harvesting and transplantation after high-dose chemotherapy.

Adult↗
PubMed2000

Resolution of psoriasis after allogeneic bone marrow transplantation for chronic myelogenous leukemia: late complications of therapy.

Treatment of autoimmune disease with bone marrow transplantation (BMT) is under investigation. A few reports of patients undergoing allogeneic BMT for malignant conditions observed the resolution of psoriasis after BMT, with minimal late morbidity. We describe a patient with chronic myelogenous leukemia (CML) whose psoriasis resolved completely after allogeneic BMT. However, the patient's course was complicated by extensive chronic graft-versus-host disease (GVHD), recurrent serious infections, poor performance status and quality of life, and severe disability. The patient died 887 days post transplant due to infectious complications. The potential benefits and risks of treatment of autoimmune diseases with allogeneic BMT are discussed.

Autoimmune Diseases↗
PubMed2000

Dolasetron for the prevention of postoperative nausea and vomiting following outpatient surgery with general anaesthesia: a randomized, placebo-controlled study. The Dolasetron PONV Prevention Study Group.

In a multicentre, randomized, double-blind, placebo-controlled dose-ranging study, 1030 patients undergoing outpatient surgery with general anaesthesia received i.v. dolasetron mesylate (12.5, 25, 50, or 100 mg) or placebo. The principal outcome measure was the proportion of patients who were free of emesis or rescue medication for the 24-h period after the study drug was given; the subsidiary outcome measure was survival time without rescue medication. Effects on nausea were quantified using a visual analogue scale. Compared with placebo, a complete response was significantly higher when all four dolasetron doses were combined (49% vs. 58%, P =0.025). In females, dolasetron, 12.5-mg, dolasetron provided maximum clinical benefit (effectiveness compared with adverse events), with no additional benefit in complete response rates or nausea visual analogue scale scores at higher doses. No significant differences were observed in complete response for any dolasetron dose in males compared with placebo. The majority of adverse events reported were mild or moderate. Dolasetron provided well-tolerated, safe, and effective prophylaxis for post-operative nausea and vomiting with maximum effectiveness observed at a dose of 12.5 mg.

Adult↗
PubMed2000

Mitochondrial Ca(2+)homeostasis in the regulation of apoptotic and necrotic cell deaths.

Using distinct models of apoptosis and necrosis, we have investigated the effect of mitochondrial Ca(2+)(Ca(m)) homeostasis in the regulation of cell death in neuroblastoma cells as well as cardiac myocytes. The steady state level of Ca(m)was determined as the FCCP-releasable Ca(2+). Culturing cells with low concentration of extracellular Ca(2+)(Ca(o)) or with EGTA triggered an early reduction in both the Ca(m)store and the membrane potential (DeltaPsi(m)). This was followed by the detection of cytochrome c release, caspase activation, and apoptosis. Inhibitors of the mitochondrial permeability transition pore such as cyclosporin A and Bcl-2 blocked the release of Ca(m)and inhibited apoptosis. In contrast, mitochondrial Ca(2+)overload resulted in necrotic cell death. Culturing cells in the presence of excess Ca(o)led to increased Ca(m)load together with a decrease of DeltaPsi(m)that reached maximum at 1 h, with necrosis occurring at 2 h. While the decline of Ca(m)and DeltaPsi(m)was a coupled reaction for apoptosis, this relationship was uncoupled during necrosis. Clonazepam, a relatively specific inhibitor of the mitochondrial Na/Ca exchanger, was able to protect the cells from necrosis by reducing Ca(m)overload. Importantly, combination of clonazepam and cyclosporin showed a cooperative effect in further reducing the Ca(m)overload and abolished cell death. The data imply the participation of Ca(m)homeostasis in the regulation of apoptosis and necrosis.

Animals↗
PubMed2000

Psychosocial correlates of cigarette smoking abstinence, experimentation, persistence and frequency during adolescence.

The purpose of this cross-sectional study was to examine and to compare the psychosocial characteristics associated with four dimensions of smoking: abstinence (never vs. ever), experimentation, frequency (daily vs. non-daily), and persistence (former vs. current). Persistent smokers (1 or more years) were contrasted with those who had been able to stop smoking for 1 year or more. From a sample of high school students who were assessed on two occasions (n = 1507), six smoking groups were defined: never smokers (n = 862), experimenters (n = 235), former non-daily (n = 80), current non-daily (n = 73), former daily (n = 71), and current daily (n = 110). The association between the four smoking dimensions and demographic, psychopathology, and psychosocial variables were examined. Differences between the never smokers and the experimenters were relatively small; albeit even minimal use of cigarettes is associated with some level of problems. As found in previous studies, smokers compared to never-smokers had substantially higher scores on most indices of dysfunction. Both frequent and persistent smoking was associated with higher lifetime prevalence of drug abuse/dependence and having more friends who smoke. Smoking persistence was uniquely related to greater conflict with parents and more problematic academic behavior. Smoking frequency was uniquely associated with higher impulsiveness. Gender did not significantly moderate the associations between smoking status and the psychosocial functioning. To the extent that there were differences between the characteristics associated with frequency and persistence, the results have implications for the design of interventions aimed at these dimensions.

Adaptation, Psychological↗
PubMed2000

Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats.

Obesity plays a pivotal role in the pathophysiology of metabolic and cardiovascular diseases. Resistance to insulin is commonly seen in metabolic disorders such as obesity and diabetes. Insulin-like growth factor-I (IGF-I) mimics insulin in many tissues and has been shown to enhance cardiac contractile function and growth. Because IGF-I resistance often accompanies resistance to insulin, we sought to determine whether IGF-I-induced myocardial contractile was elevated and whether heart and kidney size were enlarged in obese compared with lean rats. The myocyte contraction profile in the obese rats showed a decreased peak shortening associated with prolonged relengthening and normal shortening duration, a pattern similar to that observed in diabetes. IGF-I (1-500 ng/ml) caused a dose-dependent increase in peak shortening in lean but not obese animals, but it did not alter the duration of shortening and relengthening. Consistent with contractile data, IGF-I induced a dose-dependent increase in Ca(2+) transients only in myocytes of lean rats. IGF-I receptor mRNA levels were significantly reduced in obese rat hearts. These results suggest that the IGF-I-induced cardiac contractile responses are attenuated in the Zucker model of obesity. The mechanisms underlying this alteration may be related to the decreased receptor number and/or changes in intracellular Ca(2+) handling in these animals.

Animals↗
PubMed2000

The School Connection Scale: a factor analysis.

An individual's feeling of connection with a social system has been viewed by diverse traditions as an important predictor of social behavior. While some of these theoretical traditions have conceptualized and assessed a feeling of connection as a global phenomenon, more recent work has focused on the development of measures for separate contexts in which connection occurs. Using a diverse sample of 1,739 adolescents, this study examined an original scale designed specifically to assess youth's feeling of connection with school. Intercorrelations among scales were factor analyzed to examine the structural validity of elements developed from the literature and focus groups of students. The results yield for the School Connection Scale three subscales on which scores were reliable and valid and account for 49.5% of the variance.

Adolescent↗
PubMed1999

The alpha-isoform of class II phosphoinositide 3-kinase is more effectively activated by insulin receptors than IGF receptors, and activation requires receptor NPEY motifs.

Little is known about the physiological role and mechanism of activation of class II phosphoinositide 3-kinases (PI3Ks), although it has been shown that the PI3K-C2alpha isoform is activated by insulin. Using chimaeric receptor constructs which can be activated independently of endogenous receptors in transfected cells, we found that PI3K-C2alpha activity was stimulated to a greater extent by insulin receptors than IGF receptors in 3T3-L1 adipocytes. Activation of PI3K-C2alpha required an intact NPEY motif in the receptor juxtamembrane domain. We conclude that PI3K-C2alpha is a candidate for participation in insulin-specific intracellular signalling.

3T3 Cells↗
PubMed1999

Mechanical load enhances procollagen processing in dermal fibroblasts by regulating levels of procollagen C-proteinase.

Mechanical forces are emerging as key regulators of cell function. We hypothesize that mechanical load may influence dermal fibroblast activity. We assessed the direct effects of mechanical load on human dermal fibroblast procollagen synthesis and processing in vitro. Cells were loaded in a biaxial loading system (Flexercell 3000). Hydroxyproline levels were measured in the medium and cell layer as an estimate of procollagen synthesis and processing to insoluble collagen. Mechanical load (in the presence of serum or TGF-beta) enhanced procollagen synthesis by 45 +/- 3% (P < 0.001), and 38 +/- 4% (P < 0.001), respectively, over unloaded growth factor controls after 48 h. Insoluble collagen deposition was enhanced in the same cultures by 115 +/- 8% (P < 0.01) and 72% +/- 9% (P < 0.01), respectively. This effect was inhibited using l-arginine suggesting that procollagen C-proteinase, the enzyme which directly cleaves the C-terminal propeptide of procollagen to form insoluble collagen, is required for the fiber formation observed. Procollagen mRNA levels in loaded samples increased by more than two-fold in both serum and TGF-beta-treated cultures at 48 h. Procollagen C-proteinase mRNA levels were also enhanced by a similar magnitude, although the increase was observed at 24 h. Procollagen C-proteinase protein levels were also increased at this time. Protein and mRNA levels of the procollagen C-proteinase enhancer protein, which binds the C-terminal propeptide of procollagen to enhance the rate of peptide cleavage, were unaffected by mechanical load. This study demonstrates that mechanical load promotes procollagen synthesis in dermal fibroblasts by enhancing gene expression and posttranslational processing of procollagen.

Bone Morphogenetic Protein 1↗
PubMed1999

Hypertension augments ethanol-induced depression of cell shortening and intracellular Ca(2+) transients in adult rat ventricular myocytes.

Ethanol, a risk factor for myocardial dysfunction, depresses myocardial contraction. This study was to determine whether ethanol-induced myocardial depression is affected by hypertension. Mechanical properties of ventricular myocytes isolated from both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were evaluated using a video edge-detection system. Myocytes were electrically stimulated to contract at 0.5 Hz. Contractile properties analyzed include peak twitch amplitude (PTA), time-to-PTA (TPS), time-to-90% relengthening (TR(90)), and maximal velocities of shortening/relengthening (+/-dL/dt). Intracellular Ca(2+) transients were measured as fura-2 fluorescence intensity (DeltaFFI) changes. Acute ethanol exposure (80-640 mg/dl) caused a concentration-dependent inhibition of PTA and DeltaFFI in both WKY and SHR myocytes. The extent of maximal inhibition of PTA and FFI was significantly greater in SHRs (53.7 and 38.9%) compared to the WKY group (21.0 and 25.4%). Ethanol did not affect TPS but shortened TR(90) and slowed +/-dL/dt at high concentration ranges. Interestingly, the augmented ethanol-induced inhibition of cell shortening in hypertension was greatly attenuated by Ca(2+) channel opener BayK 8644 (1 microM). These results suggest that ethanol-induced myocardial depression may be augmented in hypertension, possibly due to mechanism(s) involving sarcolemmal Ca(2+) channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Insulin activates the alpha isoform of class II phosphoinositide 3-kinase.

The novel class II phosphoinositide (PI) 3-kinases are characterized by the presence of a C-terminal C2 domain, but little is known about their regulation. We find insulin causes a rapid 2-3-fold increase in the activity of PI 3-kinase C2alpha (PI3K-C2alpha) in CHO-IR cells, 3T3-L1 adipocytes, and fully differentiated L5L6 myotubes. No insulin-induced activation of PI3K-C2alpha was observed in cell types known to have low responsiveness to insulin including HEK 293 cells, 3T3-L1 preadipocytes, and undifferentiated L5L6 myoblasts. The mechanism of activation of PI3K-C2alpha by insulin differs from that of class Ia PI 3-kinases in that insulin stimulation did not cause PI3K-C2alpha to associate with IRS-1 or insulin receptor. PI3K-C2alpha existed as a doublet, and insulin stimulation caused a redistribution from the lower molecular weight band to the higher molecular weight band, suggesting phosphorylation-induced bandshift. Consistent with this, in vitro phosphatase treatment reduced the intensity of the upper band back to that seen in unstimulated cells. This suggests that insulin-induced phosphorylation could play a role in regulation of the activity of PI3K-C2alpha. The finding that insulin activates PI3K-C2alpha in cell types known to possess a wide range of responses to insulin suggests that PI3K-C2alpha is a novel component of insulin-stimulated signaling cascades.

Animals↗
PubMed1999

Role of phenytoin in wound healing--a wound pharmacology perspective.

Topical agents used for the enhancement of wound healing are designed to act locally and, therefore, do not undergo classic systemic metabolic modification. This commentary reviews the potential role of a vulnerary agent, phenytoin, (PHT), from a wound pharmacology perspective. This agent may have the potential to alter the dynamics of wound healing, suggesting a therapeutic use for the stimulation of chronic wounds. Oral PHT therapy is used widely for the treatment of convulsive disorders, and about half the patients treated develop gingival overgrowth as a side-effect. This apparent stimulatory effect has prompted its assessment in wound healing. Investigations into the mechanisms of gingival overgrowth also provide clues to its action in wound healing, and important similarities and differences are discussed. It appears also that both gingiva and skin are important extrahepatic sites for xenobiotic metabolism, and analysis of the biochemical mechanisms should lead to the design of safer analogues for wound healing. On the other hand, differences between the pharmacokinetics of topical PHT in these tissue situations indicate that different formulations are required for gingival and cutaneous wound healing and during the changing course of wound healing itself.

Administration, Topical↗
PubMed1999

A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients.

This randomized study compared the number of leukaphereses required to collect an optimal target yield of 5 x 10(6) CD34(+) peripheral blood progenitor cells/kg, using either stem cell factor (SCF) at 20 micrograms/kg/d in combination with Filgrastim at 10 micrograms/kg/d or Filgrastim alone at 10 micrograms/kg/d, from 203 patients with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield of CD34(+) cells had been reached or a maximum of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the patients treated with SCF plus Filgrastim (n = 100) compared with 47% of those receiving Filgrastim alone (n = 103) reached the CD34(+) cell target yield. There was a clinically and statistically significant reduction (P <.05) in the number of leukaphereses required to reach the target yield for the patients receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with patients receiving Filgrastim alone (median, 6 or more leukapherses; ie, <50% of patients reached the target in 5 leukaphereses). All patients receiving SCF were premedicated with antihistamines, albuterol, and pseudoephedrine. Treatment was safe, generally well tolerated, and not associated with life-threatening or fatal toxicity. In conclusion, SCF plus Filgrastim is a more effective peripheral blood progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In addition to the potential for reduced leukapheresis-related morbidity and costs, SCF offers additional options for obtaining cells for further graft manipulation.

Adult↗
PubMed1999

Adhesion, alignment, and migration of cultured Schwann cells on ultrathin fibronectin fibres.

Individual fibres of fibronectin (Fn-fibres), an extracellular matrix cell adhesion glycoprotein, were produced from a purified solution of fibronectin. These fibres range from 0.5-7 microm in width and have been engineered to produce mats (Fn-mats) by using a unidirectional shear force to orientate the fibres. Fn-fibres have been shown to promote alignment by contact guidance of human dermal fibroblasts, neurites, macrophages, and epitenon fibroblasts. Fn-mats have been used to orientate and enhance the regeneration of peripheral nerve components. We investigated cell spreading, orientation, formation of focal contacts, and the speed of cell movement on individual Fn-fibres, glass-covered with poly-L-lysine and poly-L-lysine/laminin/Fn. Fibronectin fibres significantly promoted cell spreading and the speed of cell migration with alignment of focal contacts and F-actin filaments to the axis of the fibres. The study reveals the potential of Fn-fibres to guide and direct cellular behaviour by contact guidance. The increase in migration and other behaviour exhibited by Schwann cells on Fn-fibres justifies the use of Fn-mats for peripheral nerve repair and is clinically important in that atrophy of the target organ, which is the most common failure of nerve repair, may be minimised.

Actins↗